Lipid-based platinum compounds and nanoparticles

Abstract

The present disclosure is in relation to the field of nanotechnology and cancer therapeutics. In particular, the present disclosure relates to platinum based compounds comprising platinum moiety, linker moiety and lipid moiety and corresponding nanoparticles thereof. The disclosure further relates to synthesis of said platinum based compounds, nanoparticles and compositions comprising said platinum based compounds/nanoparticles. The disclosure also relates to methods of managing cancer by employing aforesaid carbene compounds, platinum based compounds, nanoparticles and compositions thereof.

What is claimed is: 
     
       1. A compound of Formula (VIII):
   Q-linker-lipid  (VIII)
 
 wherein: 
 the linker is:
 (a) —X—CH 2 —X 2 —X 1 —, wherein X is NH; X 1  is C(O)O, C(O)NH, O(CH 2 )—O, NH, or O; X 2  is (CH 2 ) n  or C(O); and n is 0, 1, 2, 3, 4, or 5; 
 (b) —(CH 2 ) n O—, —(CH 2 ) n NHC(O)O—, —(CH 2 ) n OC(O)NH—, —(CH 2 ) n C(O)NH(CH 2 ) m O—, —(CH 2 ) n O(CH 2 ) m O—, —(CH 2 ) n O(O)—, —(CH 2 ) n NHC(O)(CH 2 ) m O—, or —(CH 2 ) n C(O)O—; wherein n and m are, independently, 0, 1, 2, 3, 4, or 5; 
 (c) —X 3 —X 4 X 5 —X 6 —, wherein X 3  is CH, CH 2 , or O; and X 4 , X 5  and X 6  are, independently,—CH 2 O— or O; or 
 (d) a combination of (a)-(c); 
 
 the lipid is a fat, wax, sterol, steroid, bile acid, fat-soluble vitamin, monoglyceride, diglyceride, phospholipid, glycolipid, sulpholipid, aminolipid, chromolipid, glycerophospholipid, sphingolipid, prenol lipid, saccharolipid, polyketide, fatty acid, or a combination thereof; 
 Q is 
 
       
         
           
           
               
               
           
         
          wherein X is NH or N(CH 2 COO − ); and Z is a platinum containing compound, wherein the platinum forms a part of the ring; 
       
       
         
           
           
               
               
           
         
          wherein X is S + , C, S + ═O, N + H, or P═O; X 1  is —CH, —CH 2  or CH 2 O; X 2  is C═O; and Z is a platinum containing compound, wherein the platinum forms a part of the ring; 
       
       
         
           
           
               
               
           
         
          wherein X 1  is (CH 2 ) n ; X 2  is C═O; Z is a platinum containing compound, wherein the platinum forms a part of the ring; and n is 0, 1, or 2; 
       
       
         
           
           
               
               
           
         
          wherein R 1 , R 2  and R 3  are, independently, halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, -linker-lipid, or a combination thereof, or R 1  and R 2  together with the Pt atom or R 2  and R 3  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl or R 1  and R 2  together with the Pt atom and R 2  and R 3  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl; or 
       
       
         
           
           
               
               
           
         
          wherein R 1 , R 2 , R 3 , R 4  and R 5  are, independently, halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, -linker-lipid, or a combination thereof, or R 1  and R 2  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl, or R 3  and R 4  together with the Pt atom form an optionally substituted cyclyl or heterocyclyl. 
       
     
     
       2. The compound of  claim 1 , wherein Z is 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are, independently, halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, or a combination thereof, or R 1  and R 2 , together with the Pt atom form an optionally substituted cyclyl or heterocyclyl. 
     
     
       3. The compound of  claim 2 , wherein Z is 
       
         
           
           
               
               
           
         
       
       wherein p is 0, 1, 2, or 3. 
     
     
       4. The compound of  claim 1 , wherein the linker is a bond, ethylene diamine, ethylene glycol, diethylene glycol, 1,3-propanediol, glycine, beta alanine, —O—, —CH 2 O—HCH 2 CH 2 NHC(O)—, —NHCH 2 CH 2 NHC(O)O—, —NHCH 2 CH 2 —, —NHCH 2 CH 2 O—, —NHCH 2 C(O)—, —NHCH 2 C(O)O—, —NHCH 2 C(O)OCH 2 CH 2 CH 2 —, —NHCH 2 C(O)OCH 2 CH 2 CH 2 O—, —NHCH 2 C(O)NH—, —CH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 CH 2 NHC(O)—, —CH 2 CH 2 NHC(O)O—, —CH 2 CH 2 O—, —CH 2 C(O)NHCH 2 CH 2 —, —CH 2 C(O)NHCH 2 CH 2 O—, —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 OCH 2 CH 2 O—, —CH 2 C(O)—, —CH 2 C(O)O—, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 O—, ═CH—CH═CH 2 —, ═CH—CH═CHCH 2 O—, —CH═CHCH 2 —, —CH═CHCH 2 O—, —OCH 2 CH 2 O—, —CH 2 —, —CH 2 O—, —NHC(O)CH 2 —, —NHC(O)CH 2 O—, —C(O)CH 2 —, —C(O)CH 2 O—, —OC(O)CH 2 —, —OC(O)CH 2 O—, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 —, —OC(O)CH 2 CH 2 C(O)NHCH 2 CH 2 —, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 O—, —OC(O)CH 2 CH 2 C(O)NHCH 2 CH 2 O—, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)—, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)—, —C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)O—, —OC(O)CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)O—, or a combination thereof. 
     
     
       5. The compound of  claim 1 , wherein the lipid is cholesterol or alphatocopherol. 
     
     
       6. The compound of  claim 1 , wherein the compound is of:
 (i) Formula I: 
 
       
         
           
           
               
               
           
         
         wherein,
 X is NH; 
 X 1  is COOH, CONH 2 , O—(CH 2 ) n —OH, NH 2  or OH; 
 X 2  is (CH 2 ) n  or CO; 
 X 3  is (CH 2 ) n , CH 2 —NH or C 4 H 8 ; 
 X 4  is CO or —CH—CH 3 ; and 
 Z is platinum containing compound, wherein the platinum forms a part of the Formula I ring; and 
 n is 0, 1, or 2; 
 
         (ii) Formula II: 
       
       
         
           
           
               
               
           
         
         wherein,
 X is NH or N—CH 2 COO − ; 
 X 1  is —(CH 2 ) n OH, —(CH 2 ) n NHCOOH, —(CH 2 ) n CONH(CH 2 ) n OH, (CH 2 ) n O(CH 2 ) n OH, (CH 2 ) n C═O, —(CH 2 ) n NHCO(CH 2 ) n OH or (CH 2 ) n —COOH; 
 Z is platinum containing compound, wherein the platinum forms a part of the Formula II ring; and 
 n is 0, 1, or 2; 
 
         (iii) Formula III: 
       
       
         
           
           
               
               
           
         
         wherein,
 X is S + , C, S + ═O, N + H or P═O; 
 X 1  is —CH, —CH 2  or —CH 2 O; 
 X 2  is C═O; 
 X 3  is CH, CH 2  or O; 
 X 4 , X 5 , X 6  is —CH 2 O or O; and 
 Z is platinum containing compound, wherein the platinum forms a part of the Formula III ring; 
 
         (iv) Formula IV: 
       
       
         
           
           
               
               
           
         
         wherein,
 X is CH 2 OH; 
 X 1  is (CH 2 ) n ; 
 X 2  is C═O; 
 Z is platinum containing compound, wherein the platinum forms a part of the Formula IV ring; and 
 n is 0, 1, or 2; 
 
         (v) Formula VI: 
       
       
         
           
           
               
               
           
         
          or 
         (vi) Formula VII: 
       
       
         
           
           
               
               
           
         
       
     
     
       7. A nanoparticle comprising a compound of  claim 1 . 
     
     
       8. The nanoparticle of  claim 7 , wherein the nanoparticle further comprises a co-lipid and/or stabilizer. 
     
     
       9. A method of treating or managing cancer in a subject, the method comprising administering a therapeutically effective amount of a compound of  claim 1  to a subject in need thereof. 
     
     
       10. The compound of  claim 1 , which is 
       
         
           
           
               
               
           
         
       
     
     
       11. The compound of  claim 1 , wherein the lipid is a sterol that is cholesterol, cholesterol chloroformate or a derivative thereof, or a combination thereof. 
     
     
       12. The method of  claim 9 , wherein the cancer is breast cancer, ovarian cancer, a glioma, gastrointestinal cancer, prostate cancer, lung carcinoma, hepatocellular carcinoma, testicular cancer, cervical cancer endometrial cancer, bladder cancer, head and neck cancer, or gastro-esophageal cancer.